Pharmaceutical composition

ABSTRACT

An object of the present invention is to provide a pharmaceutical composition which has excellent stability, disintegratability, and absorbability, is easily prepared, and contains 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative. The present invention relates to a pharmaceutical composition containing 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide or a pharmaceutically acceptable salt thereof and hydroxypropyl-β-cyclodextrin.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin, particularly a pharmaceutical compositionfor oral administration.

BACKGROUND ART

Cyclodextrins and derivatives thereof are widely generally known as anexcipient for improving the solubility of a hydrophobic compound inwater. However, most of them are liquid formulations in which the wholeor a part of a hydrophobic compound is included inside a cyclodextrin.Therefore, a solid formulation in which a cyclodextrin or a derivativethereof is physically added to improve the solubility is not well known.

At present, as a compound having excellent c-Met/VEGFR2 inhibitoryactivity and showing antitumor activity,4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide(hereinafter, also referred to as “compound 1”) has been reported (PTL 1and 2, and NPL 1 and 2). It has also been reported that the compound 1is useful as a therapeutic agent for osteoporosis (PTL 3). Further,mesylates of the compound 1 and crystals thereof have also been reported(PTL 4).

However, these reports contain no mention of a pharmaceuticalcomposition containing the compound 1 or a pharmaceutically acceptablesalt thereof and a cyclodextrin or a derivative thereof.

CITATION LIST Patent Literature

PTL 1: WO 2009/125597

PTL 2: WO 2013/100014

PTL 3: WO 2015/046484

PTL 4: WO 2016/175305

Non Patent Literature

NPL 1: Molecular Cancer Therapeutics; 12 (12); pp. 2685-96, 2013

NPL 2: European Journal of Cancer; 48 (6); p. 94; 2012

SUMMARY OF INVENTION Technical Problem

The present invention provides a pharmaceutical composition which hasexcellent stability, disintegratability, and absorbability, is easilyprepared, and contains the compound 1 or a pharmaceutically acceptablesalt thereof.

Solution to Problem

In view of this, the present inventor found that by addinghydroxypropyl-β-cyclodextrin (HP-β-CD) to the compound 1 or apharmaceutically acceptable salt thereof, a pharmaceutical compositionwhich has excellent stability, has excellent stability,disintegratability, and absorbability, and is easily prepared can beobtained, and thus completed the present invention.

That is, the present invention relates to the following [1] to [35].

[1] A pharmaceutical composition, containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-β-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

[2] The pharmaceutical composition according to [1], wherein thecomposition includes peaks at at least 5 or more diffraction angles 2θ(±0.2°) selected from 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and26.0 (°) in powder X-ray structure diffraction.

[3] The pharmaceutical composition according to [1] or [2], wherein thecomposition includes peaks at diffraction angles 2θ (±0.2°) of 6.5, 7.8,9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°) in powder X-raystructure diffraction.

[4] The pharmaceutical composition according to any one of [1] to [3],wherein the composition includes peaks at chemical shift values [δ(ppm)] of 162.6, 130.4, 103.1, 82.7, 73.3, 41.9, and 19.9 in solid¹³C-NMR.

[5] The pharmaceutical composition according to any one of [1] to [4],wherein the composition includes peaks at at least 5 or more absorptionbands selected from 1663, 1352, 1225, 1156, 1032, 720, and 553 (cm⁻¹) inan infrared absorption spectrum.

[6] The pharmaceutical composition according to any one of [1] to [5],wherein hydroxypropyl-β-cyclodextrin is contained at 0.1 to 5.5 parts bymass with respect to 1 part by mass of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof.

[7] The pharmaceutical composition according to any one of [1] to [6],further containing a silicic acid derivative.

[8] The pharmaceutical composition according to any one of [1] to [7],further containing a cellulose derivative.

[9] The pharmaceutical composition according to any one of [1] to [8],wherein the pharmaceutical composition is a tablet or a granule.

[10] The pharmaceutical composition according to any one of [1] to [9],wherein the pharmaceutical composition is for oral administration.

[11] The pharmaceutical composition according to any one of [1] to [10],wherein the pharmaceutical composition is a tablet.

[12] The pharmaceutical composition according to any one of [1] to [10],wherein the pharmaceutical composition is a tablet having a maximumdiameter of 5 mm or less.

[13] A pharmaceutical composition, containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin, the pharmaceutical composition produced byphysical mixing.

[14] The pharmaceutical composition according to [13], wherein thephysical mixing is a production method that does not include a step inwhich4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof is converted into asolution state when the pharmaceutical composition is produced.

[15] The pharmaceutical composition according to [13] or [14], whereinthe physical mixing is mixing or granulation.

[16] The pharmaceutical composition according to any one of [13] to[15], wherein the physical mixing is mixing, a dry granulation method,or a wet granulation method.

[17] The pharmaceutical composition according to any one of [13] to[16], wherein the physical mixing is mixing, a crushing granulationmethod, a fluidized bed granulation method, a rolling bed granulationmethod, an extrusion granulation method, or a high shear granulationmethod.

[18] The pharmaceutical composition according to any one of [13] to[17], wherein the physical mixing is a fluidized bed granulation method.

[19] The pharmaceutical composition according to any one of [13] to[18], wherein the composition includes peaks at at least 5 or morediffraction angles 2θ (±0.2°) selected from 6.5, 7.8, 9.6, 12.4, 18.8,21.2, 23.0, 24.5, and 26.0 (°) in powder X-ray structure diffraction.

[20] The pharmaceutical composition according to any one of [13] to[19], wherein the composition includes peaks at diffraction angles 2θ(±0.2°) of 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°) inpowder X-ray structure diffraction.

[21] The pharmaceutical composition according to any one of [13] to[20], wherein the composition includes peaks at chemical shift values [δ(ppm)] of 162.6, 130.4, 103.1, 82.7, 73.3, 41.9, and 19.9 in solid¹³C-NMR.

[22] The pharmaceutical composition according to any one of [13] to[21], wherein the composition includes peaks at at least 5 or moreabsorption bands selected from 1663, 1352, 1225, 1156, 1032, 720, and553 (cm⁻¹) in an infrared absorption spectrum.

[23] The pharmaceutical composition according to any one of [13] to[22], wherein hydroxypropyl-β-cyclodextrin is contained at 0.1 to 5.5parts by mass with respect to 1 part by mass of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof.

[24] The pharmaceutical composition according to any one of [13] to[23], further containing a silicic acid derivative.

[25] The pharmaceutical composition according to any one of [13] to[24], further containing a cellulose derivative.

[26] The pharmaceutical composition according to any one of [13] to[25], wherein the pharmaceutical composition is a granule.

[27] The pharmaceutical composition according to any one of [13] to[26], wherein the pharmaceutical composition is for oral administration.

[28] The pharmaceutical composition according to any one of [13] to[27], wherein the pharmaceutical composition is a tablet.

[29] The pharmaceutical composition according to any one of [13] to[28], wherein the pharmaceutical composition is a tablet having amaximum diameter of 5 mm or less.

[30] A method for producing a pharmaceutical composition, obtainable byperforming physical mixing of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

[31] The production method according to [30], wherein the physicalmixing is a production method that does not include a step in which4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof is converted into asolution state when the pharmaceutical composition is produced.

[32] The production method according to [30] or [31], wherein thephysical mixing is mixing or granulation.

[33] The production method according to any one of [30] to [32], whereinthe physical mixing is mixing, a dry granulation method, or a wetgranulation method.

[34] The production method according to any one of [30] to [33], whereinthe physical mixing is mixing, a crushing granulation method, afluidized bed granulation method, a rolling bed granulation method, anextrusion granulation method, or a high shear granulation method.

[35] The production method according to any one of [30] to [34], whereinthe physical mixing is a fluidized bed granulation method.

The present invention also relates to the following aspects.

A pharmaceutical composition for preventing and/or treating a tumor,containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

An antitumor agent, containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

Use of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin for producing an antitumor agent.

A method for preventing and/or treating a tumor, including a step ofadministering a pharmaceutical composition containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin to a subject in an effective amount for thetreatment and/or prevention.

Use of a pharmaceutical composition containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin for preventing and/or treating a tumor.

A pharmaceutical composition for inhibiting c-Met and/or VEGFR2,containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

An inhibitor for c-Met and/or VEGFR2, containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin.

Use of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin for producing an inhibitor for c-Met and/orVEGFR2.

Use of a pharmaceutical composition containing4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin for inhibiting c-Met and/or VEGFR2.

In these aspects, the above-mentioned features of the invention of thisapplication can be included.

Advantageous Effects of Invention

According to the present invention, a pharmaceutical composition whichhas excellent stability, disintegratability, and absorbability, iseasily prepared, and contains the compound 1 or a pharmaceuticallyacceptable salt thereof and a cyclodextrin derivative can be provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the results of powder X-ray diffraction spectrum (XRD)measurement of a mesylate salt of the compound 1.

FIG. 2 shows the results of XRD measurement of HP-β-CD.

FIG. 3 shows the results of XRD measurement of a physically mixedproduct of a mesylate salt of the compound 1 and HP-β-CD.

FIG. 4 shows the results of XRD measurement of a spray-dried product ofa mesylate salt of the compound 1 and HP-β-CD.

FIG. 5 shows the results of solid proton nuclear magnetic resonance(¹³C-NMR) measurement of a mesylate salt of the compound 1.

FIG. 6 shows the results of ^(—)C-NMR measurement of HP-β-CD.

FIG. 7 shows the results of ¹³C-NMR measurement of a physically mixedproduct of a mesylate salt of the compound 1 and HP-β-CD.

FIG. 8 shows the results of infrared absorption spectrum (IR)measurement of a mesylate salt of the compound 1.

FIG. 9 shows the results of IR measurement of HP-β-CD.

FIG. 10 shows the results of IR measurement of a physically mixedproduct of a mesylate salt of the compound 1 and HP-β-CD.

FIG. 11 shows the results of IR measurement in the fingerprint regionsof a mesylate salt of the compound 1, HP-β-CD, and a physically mixedproduct of the mesylate salt of the compound 1 and HP-β-CD in this orderfrom the top.

DESCRIPTION OF EMBODIMENTS

An active ingredient of the pharmaceutical composition of the presentinvention is the compound 1. The compound 1 is4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideand the structure thereof is shown below.

As the pharmaceutically acceptable salt of the compound 1 to be used inthe present invention, salts such as acid addition salts areexemplified, and preferred is a mesylate salt, and more preferred ismono mesylate.

The compound 1 or a pharmaceutically acceptable salt thereof may be asolvate (for example, a hydrate or the like) or a non-solvate, and inthe present invention, both are included in “the compound 1 or apharmaceutically acceptable salt thereof”. The compound 1 or apharmaceutically acceptable salt thereof can be produced by a methoddescribed in, for example, PTL 1 or 4.

The compound 1 or a pharmaceutically acceptable salt thereof to be usedin the present invention is contained in an amount of preferably 67 mass% or less, more preferably from 5 to 40 mass %, further more preferablyfrom 10 to 20 mass % with respect to the total pharmaceuticalcomposition.

In the cyclodextrin derivative, not only α-cyclodextrin (α-CD),β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD), but alsohydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin(SBE-β-CD), and the like are included. However, from the viewpoint ofdissolubility, stability, absorbability, etc., the cyclodextrinderivative of the present invention is hydroxypropyl-β-cyclodextrin. Theamount of hydroxypropyl-β-cyclodextrin to be used in the presentinvention may be any as long as the absorbability of the compound 1 or apharmaceutically acceptable salt thereof to be used in the presentinvention is improved, and the toxicity of hydroxypropyl-β-cyclodextrinis not appeared.

The amount of hydroxypropyl-β-cyclodextrin to be used in the presentinvention is preferably 30 mass % or more, more preferably from 60 to 95mass %, further more preferably from 76 to 85 mass % with respect to thetotal pharmaceutical composition.

The amount of hydroxypropyl-β-cyclodextrin to be used in the presentinvention is preferably from 0.1 to 5.5 parts by mass, more preferablyfrom 4.0 to 5.0 parts by mass with respect to 1 part by mass of thecompound 1 or a pharmaceutically acceptable salt thereof

As the pharmaceutical composition of the present invention, acomposition in which the compound 1 or a pharmaceutically acceptablesalt thereof and hydroxypropyl-β-cyclodextrin do not form a clathrate orpartially form a clathrate is exemplified. That is, it can be confirmedby a powder X-ray diffraction spectrum, solid NMR, IR, etc. that in thepharmaceutical composition of the present invention, one in which thecompound 1 or a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin do not form a clathrate is present.

In addition, an error of a peak at a diffraction angle 2θ in a powderX-ray diffraction spectrum in the present invention is about ±0.2°. Thisis an error caused by an apparatus used in measurement, preparation of asample, a data analysis method, or the like. Therefore, when a crystalis subjected to XRD measurement in the present invention, an error of±0.2° of the obtained diffraction angle 2θ is taken into consideration.Further, for the same reason, in the present invention, an error of apeak at a chemical shift (ppm) in a solid ¹³C-NMR chart is about ±1.0ppm, and an error of a peak at an absorption band (cm⁻¹) in an infraredabsorption spectrum is about ±2 cm⁻¹.

The pharmaceutical composition of the present invention hascharacteristic peaks at at least 5 or more diffraction angles (2θ±0.2°)selected from 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°)in powder X-ray diffraction, preferably has characteristic peaks atdiffraction angles (2θ±0.2°) of 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0,24.5, and 26.0 (°).

The pharmaceutical composition of the present invention preferably hascharacteristic peaks at chemical shift values [δ (ppm)] of 162.6, 130.4,103.1, 82.7, 73.3, 41.9, and 19.9 in a solid ¹³C-NMR chart.

The pharmaceutical composition of the present invention preferably hascharacteristic peaks at at least 5 or more absorption bands selectedfrom 1663, 1352, 1225, 1156, 1032, 720, and 553 (cm⁻¹) in an infraredabsorption spectrum, more preferably has characteristic peaks atabsorption bands of 1663, 1352, 1225, 1156, 1032, 720, and 553 (cm⁻¹).

The pharmaceutical composition of the present invention can be producedby physical mixing. The physical mixing refers to a production methodthat does not include a step in which the compound 1 or apharmaceutically acceptable salt thereof is converted into a solutionstate when the pharmaceutical composition is produced. As the physicalmixing, mixing to form a uniform composition by applying an appropriateoperation to two or more types of solids containing the compound 1 or apharmaceutically acceptable salt thereof, a granulation that isperformed when the compound 1 or a pharmaceutically acceptable saltthereof is in a solid state, and the like are exemplified.

Examples of a granulation method that can be used when thepharmaceutical composition of the present invention is produced includea dry granulation method and a wet granulation method. Specific examplesof the dry granulation method include a crushing granulation method.Further, examples of the wet granulation method include a fluidized bedgranulation method, a rolling bed granulation method, an extrusiongranulation method, and a high shear granulation method, and preferredis a fluidized bed granulation method.

In the physical mixing, a solvent can be added as needed. As the type ofthe solvent, water, ethanol, a water-ethanol mixed solution, and thelike are exemplified, and preferred is water. When such a solvent isused in the physical mixing, the pharmaceutical composition of thepresent invention may be used as it is or after it is dried.

In the physical mixing, a fluidizer or the like can be further added.Examples of the fluidizer include silicic acid derivatives such as lightanhydrous silicic acid, calcium silicate, magnesium aluminometasilicate,talc, aluminum silicate, and hydrated silicon dioxide, and preferred islight anhydrous silicic acid.

In the physical mixing, a binder can be added. As the binder, acellulose derivative, starch, povidone, or polyvinyl alcohol can beexemplified. Examples of the cellulose derivative include hydroxypropylcellulose, hypromellose, and methylcellulose, and preferred ishydroxypropyl cellulose.

Here, the amount of the fluidizer to be used in the present invention isgenerally 10 mass % or less, preferably from 0.1 to 2 mass %, morepreferably from 0.2 to 1 mass % with respect to the total pharmaceuticalcomposition.

Examples of the pharmaceutical composition of the present inventioninclude a tablet, a granule, a powder, and a fine granule, and preferredis a tablet or a granule. In the tablet, the granule, the powder, andthe fine granule, a powdery granular material that is rapidly dissolvedin the oral cavity and can be taken without water is included.

Further, as the pharmaceutical composition of the present invention, atablet can be adopted. The tablet can also be produced using commonlyknown excipients, and it is also possible to prepare a tablet from theabove-mentioned granule using commonly known methods. As the shape ofthe tablet, a generally used shape such as a cylindrical shape, a diskshape, a lenticular shape, or a rod-like shape can be adopted. The sizeof the tablet is not particularly limited as long as a human can orallytake it, however, the maximum diameter (diameter) is preferably 15 mm orless, more preferably 10 mm or less. Further, in consideration ofabsorbability and administration to children, etc., the maximum diameteris further more preferably 5 mm or less. Further, in consideration ofthe absorbability and the ease of adjustment of the pharmaceuticalcomposition of the present invention, a tablet having a cylindricalshape with a maximum diameter of 4 mm or less is preferred. The lowerlimit of the maximum diameter of the tablet is not particularly limited,but is generally 2 mm or more from the viewpoint of handling.

Further, when a tablet having a cylindrical shape with a diameter of 5mm or less is adopted as the pharmaceutical composition of the presentinvention, the weight of the compound 1 per tablet is 10 mg or less fromthe viewpoint of the size and the absorbability of the tablet. Afterpreparation of the tablet, an operation of packing a plurality oftablets in one package is sometimes generated. In that case, if there isa large difference in the diameter and the thickness of the cylindricalshape, it takes time when adjusting the packing amount by a countingplate with holes, and during the process, a few tablets may enter thehole of the counting plate or no tablet may enter the hole, andtherefore, excess or shortage of the packing amount may occur.Therefore, in the case of the tablet having a cylindrical shape with adiameter of 5 mm or less, the ratio of the thickness to the diameter ofthe cylindrical shape is typically from 60 to 140% as an example,preferably from 80 to 120%.

Further, in the pharmaceutical composition of the present invention,other than the compound 1 or a pharmaceutically acceptable salt thereofand hydroxypropyl-β-cyclodextrin, other excipients may be blended asneeded. The excipients are not particularly limited as long as it isgenerally used in drug products in the pharmaceutical field, and forexample, a fluidizer, a diluent, a binder, a disintegrant, a lubricant,a coating agent, a colorant, a flavor, a taste masking agent, and thelike can be exemplified, however, it is not limited thereto.

The pharmaceutical composition of the present invention is useful as anantitumor agent because the compound 1 has excellent c-Met inhibitoryactivity and VEGFR2 inhibitory activity. A target cancer is notparticularly limited, however, examples thereof include head and neckcancer, gastrointestinal cancer [for example, esophageal cancer, gastriccancer, gastrointestinal stromal tumors, duodenal cancer, liver cancer,biliary tract cancer (for example, gallbladder and bile duct cancer,etc.), pancreatic cancer, small intestine cancer, large bowel cancer(for example, colorectal cancer, colon cancer, rectal cancer, etc.),etc.], lung cancer, breast cancer, ovarian cancer, uterine cancer (forexample, cervical cancer, endometrial cancer, etc.), kidney cancer,bladder cancer, prostate cancer, urothelial cancer, bone and soft tissuesarcoma, blood cancer (for example, B cell lymphoma, chronic lymphocyticleukemia, peripheral T-cell lymphoma, myelodysplastic syndrome, acutemyelogenous leukemia, acute lymphocytic leukemia, etc.), multiplemyeloma, skin cancer, and mesothelioma.

EXAMPLES

Hereinafter, the present invention will be further specificallydescribed with reference to Examples, however, the invention is notlimited thereto. Although the invention is sufficiently described byExamples, it is to be understood that various changes and modificationscan be made by a person skilled in the art. Therefore, such changes ormodifications are included in the invention unless they depart from thescope of the invention.

As various types of reagents used in Examples, commercially availableproducts were used unless otherwise indicated.

Powder X-Ray Diffraction Spectrum (XRD) Measurement

Powder X-ray diffraction was performed by lightly crushing anappropriate amount of a test specimen in an agate mortar according toneed and then performing measurement according to the following testconditions.

Apparatus: RINT-2100 Ultima/PC (manufactured by Rigaku Corporation)

Target: CuKα

Scanning range: 5.0 to 40.0°

Sampling width: 0.02°

Scanning speed: 2°/min

The handling of the apparatus including data processing was performedaccording to the method and procedure designated for each apparatus.

Proton Nuclear Magnetic Resonance (¹³C-NMR) Measurement

¹³C-NMR measurement was performed by CMX-300 Infinity (75.188829 MHz,manufactured by Chemagnetic, Inc.) using tetramethylsilane as aninternal reference in the case where tetramethylsilane was contained ina deuterated solvent, and using an NMR solvent as an internal referencein the other cases. In each ¹³C-NMR chart obtained, all the δ valueswere expressed in ppm.

Infrared Absorption Spectrum (IR) Measurement

IR measurement was performed using FT-730 (HORIBA, Ltd.) by the KBrmethod.

[Test Example 1] Solubility Test 1 Formulation Example 1

HP-β-CD (0.5925 g) was dissolved in a diluted McIlvaine buffer at pH 3.0(50 mL), followed by heating to 37° C., whereby a test solution wasobtained.

Comparative Example 1

A test solution was obtained by heating a diluted McIlvaine buffer at pH3.0 (50 mL) to 37° C.

Comparative Example 2

A test solution was obtained in the same manner as in FormulationExample 1 using γ-CD (0.5925 g) in place of HP-β-CD (0.5925 g).

Comparative Example 3

A test solution was obtained in the same manner as in FormulationExample 1 using SBE-β-CD (0.5925 g) in place of HP-β-CD (0.5925 g).

With respect to Formulation Example 1, Comparative Example 1, andComparative Example 2, the solubility of the compound 1 over time wasmeasured. To each of the test solutions, a mesylate salt of the compound1 (0.1185 g) was added, followed by stirring at 37° C. using a magneticstirrer. The compositions of Formulation Example 1, Comparative Example1, Comparative Example 2, and Comparative Example 3 are shown in Table1.

TABLE 1 Formu- Compar- Compar- Compar- lation ative ative ative (unit:parts by mass) Example 1 Example 1 Example 2 Example 3 Mesylate salt of1.0 1.0 1.0 1.0 Compound 1 HP-β-CD 5.0 — — — γ-CD — — 5.0 — SBE-β-CD — —— 5.0

The concentration of the compound 1 in the test solution was measuredafter 30, 60, 120, and 240 minutes from the start of the test usingliquid chromatography (HPLC) under the following conditions.

Apparatus: Alliance 2690 (manufactured by Waters, Inc.)

Mobile phase A: 10 mM Na₂HPO₄ aqueous solution (pH 6.5)

Mobile phase B: acetonitrile

Gradient: mobile phase A/mobile phase B=6/4 (v/v)

Column: L-column 2 ODS, 100 mm×3.0 mm, i.d.: 3 μm

Measurement wavelength: 240 nm

The handling of the apparatus including data processing was performedaccording to the method and procedure designated for each apparatus. Theresults are shown in Table 2.

TABLE 2 After After After After 30 min 60 min 120 min 240 min μg/mLμg/mL μg/mL μg/mL Formulation Example 1 269.18 231.32 240.58 220.64Comparative Example 1 17.65 15.89 14.61 11.29 Comparative Example 2107.58 129.08 114.78 98.46

As shown in Table 2, it was found that when the same amount of acyclodextrin derivative is present, HP-β-CD shows a higher solubilitythan γ-CD. On the other hand, in the case of SBE-β-CD, the error of theconcentration of the compound 1 at each measurement time is large, andit is difficult to predict the absorbability thereof when it isadministered to a human, and therefore, it was found that SBE-β-CD isnot suitable for formulation with the compound 1.

[Test Example 2] Solubility Test 2 Formulation Example 2

A test solution was obtained in the same manner as in FormulationExample 1 using HP-β-CD (0.0593 g) in place of HP-β-CD (0.5925 g).

Formulation Example 3

A test solution was obtained in the same manner as in FormulationExample 1 using HP-β-CD (0.1185 g) in place of HP-β-CD (0.5925 g).

Formulation Example 4

A test solution was obtained in the same manner as in FormulationExample 1 using HP-β-CD (0.3555 g) in place of HP-β-CD (0.5925 g).

With respect to Formulation Examples 1 to 4, the solubility of thecompound 1 over time was measured in the same manner as in the TestExample 1. To each of the test solutions, a mesylate salt of thecompound 1 (0.1185 g) was added, followed by stirring at 37° C. using amagnetic stirrer. The compositions of Formulation Examples 1 to 4 areshown in Table 3.

TABLE 3 Formu- Formu- Formu- Formu- lation lation lation lation (unit:parts by mass) Example 1 Example 2 Example 3 Example 4 Mesylate salt of1.0 1.0 1.0 1.0 Compound 1 HP-β-CD 5.0 0.5 1.0 3.0

The concentration of the compound 1 in the test solution was measuredafter 30, 60, 120, and 240 minutes from the start of the test usingliquid chromatography (HPLC) under the same conditions. The results areshown in Table 4.

TABLE 4 After After After After 30 min 60 min 120 min 240 min μg/mLμg/mL μg/mL μg/mL Formulation Example 1 269.18 231.32 240.58 220.64Formulation Example 2 39.04 30.94 35.96 30.24 Formulation Example 359.56 61.58 54.60 50.36 Formulation Example 4 137.36 139.50 157.22140.02

As shown in Table 4, it was found that the solubility of the mesylatesalt of the compound 1 is improved in the presence of HP-β-CD, and itshows a higher solubility as HP-β-CD is present in a larger amount.

[Test Example 3] XRD Measurement Formulation Example 5

A physically mixed product (26.6 g, PM product) of a mesylate salt ofthe compound 1 was obtained by mixing the mesylate salt of the compound1 (5.0 g) and HP-β-CD (22.8 g) in a mortar.

The results of powder X-ray diffraction spectrum (XRD) measurement ofthe mesylate salt of the compound 1 are shown in FIG. 1, the results ofXRD measurement of HP-β-CD are shown in FIG. 2, the results of XRDmeasurement of the physically mixed product of the mesylate salt of thecompound 1 and HP-β-CD obtained in Formulation Example 5 are shown inFIG. 3, and the XRD measurement of a spray-dried product of the mesylatesalt of the compound 1 and HP-β-CD obtained in Comparative Example 4described below are shown in FIG. 4.

Based on these, it was found that in the XRD measurement of thephysically mixed product of the mesylate salt of the compound 1 andHP-β-CD, the product has characteristic peaks at diffraction angles(2θ±0.2°) of 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°)derived from the mesylate salt of the compound 1.

[Test Example 4] ¹³C-NMR Measurement

The results of solid proton nuclear magnetic resonance (¹³C-NMR)measurement of the mesylate salt of the compound 1 are shown in FIG. 5,the results of ¹³C-NMR measurement of HP-β-CD are shown in FIG. 6, andthe results of ¹³C-NMR measurement of the physically mixed product ofthe mesylate salt of the compound 1 and HP-β-CD obtained in FormulationExample 5 are shown in FIG. 7.

Based on these, it was found that in the solid proton nuclear magneticresonance (^(—)C-NMR) measurement of the physically mixed product of themesylate salt of the compound 1 and HP-β-CD, the product hascharacteristic peaks at chemical shift values [δ (ppm)] of 162.6, 130.4,103.1, 82.7, 73.3, 41.9, and 19.9 derived from the mesylate salt of thecompound 1.

[Test Example 5] IR Measurement

The results of infrared absorption spectrum (IR) measurement of themesylate salt of the compound 1 are shown in FIG. 8, the results of IRmeasurement of HP-β-CD are shown in FIG. 9, and the results of IRmeasurement of the physically mixed product of the mesylate salt of thecompound 1 and HP-β-CD obtained in Formulation Example 5 are shown inFIG. 10. Further, IR measurement in the fingerprint regions thereof isshown in FIG. 11.

Based on these, it was found that in the infrared absorption spectrummeasurement of the physically mixed product of the mesylate salt of thecompound 1 and HP-β-CD, the product has characteristic peaks atabsorption bands (cm⁻¹) of 1663, 1352, 1225, 1156, 1032, 720, and 553derived from the mesylate salt of the compound 1.

[Test Example 6] Stability Test Comparative Example 4

A mesylate salt of the compound 1 (5.0 g) and HP-β-CD (22.8 g) weredissolved in a mixed solution of water (100.0 g), ethanol (250.0 g) anddichloromethane (150.0 g), followed by spray drying by a spray dryer(GB22, manufactured by Yamato Scientific Co., Ltd.), whereby aspray-dried product (19.2 g, SD product) of the mesylate salt of thecompound 1 was obtained.

The compositions and the preparation methods of Formulation Example 5and Comparative Example 4 are shown in Table 5.

TABLE 5 Formulation Comparative (unit: parts by mass) Example 5 Example4 Mesylate salt of Compound 1 1.0 1.0 HP-β-CD 4.6 4.6 Preparation methodPM product SD product

With respect to Formulation Example 5 and Comparative Example 4, achange in the total amount of the related substances of the compound 1in each formulation over time was evaluated. Each formulation waswrapped with a polyethylene/cellophane laminated film and then enclosedin an aluminum bag with a desiccant and an deoxygenating agent, and theconcentration of the compound 1 in the formulations stored at 5, 25, and40° C. for 1 month and the formulations stored at 60° C. for 1 week wasmeasured using liquid chromatography (HPLC) under the followingconditions.

Apparatus: Alliance 2690 (manufactured by Waters, Inc.)

Mobile phase A: 10 mM Na₂HPO₄ aqueous solution (pH 6.5)

Mobile phase B: acetonitrile

Gradient: shown in Table 6

Column: L-column 2 ODS, 150 mm×4.6 mm, i.d.: 5 μm

Measurement wavelength: 220 nm

TABLE 6 Time (min) Mobile phase A (%) Mobile phase B (%) 0 64 36 1 64 3611 55 45 16 52 48 20 37 63 30 37 63 31 64 36 40 64 36

The handling of the apparatus including data processing was performedaccording to the method and procedure designated for each apparatus. Theresults are shown in Table 7.

TABLE 7 5° C. 25° C. 40° C. 60° C. 0 value 1 month 1 month 1 month 1week Formulation 0.25 0.37 0.39 0.38 0.30 Example 5 Comparative 1.271.45 2.10 3.15 3.18 Example 4

As shown in Table 7, it was found that the physically mixed product ofthe mesylate salt of the compound 1 and HP-β-CD has excellent stabilityas compared with the spray-dried product.

[Test Example 7] Absorbability Test 1 Comparative Example 5

Granulation was performed using a high shear granulator (FM-VG-25,manufactured by Powrex Corporation) while adding a 14% povidone solution(466 g) to a mesylate salt of the compound 1 (1564.2 g), D-mannitol(1188 g), and sodium starch glycolate (33 g), whereby a wet powder wasobtained. The wet powder was dried using a fluidized bed granulator(NFLO-5, manufactured by Freund Corporation), and then mixed using amixer (CV-20, manufactured by Tokuju Corporation) with sodium starchglycolate (158.4 g) and magnesium stearate (26.4 g), whereby granulesfor tableting were obtained. The granules for tableting were compressedinto tablets using a tableting machine (VELG 0512SW2MZ, manufactured byKikusui Seisakusho Ltd.), and thereafter, a coating solution obtained byadding hypromellose (64.8 g), macrogol 6000 (8.1 g), titanium oxide (8.1g), and yellow ferric oxide (0.081 g) was sprayed thereon using acoating machine (DRC-300, manufactured by Powrex Corporation), wherebycoated tablets were obtained.

The compositions and the preparation methods of Formulation Example 5,Comparative Example 4, and Comparative Example 5 are shown in Table 8.

TABLE 8 Formulation Comparative Comparative (unit: parts by mass)Example 5 Example 4 Example 5 Mesylate salt of Compound 1 1.0 1.0 1.0 HP-β-CD 4.6 4.6 — D-mannitol — — 0.76 Sodium starch glycolate — — 0.12Povidone — — 0.04 Magnesium stearate — — 0.02 Hypromellose — — 0.04Preparation method PM product SD product PM product

With respect to Formulation Example 5, Comparative Example 4, andComparative Example 5, each formulation was administered to animalsunder the following conditions, and the absorbability was evaluated.

Animals used: beagle dogs (3 male animals, Kitayama Labes Co., Ltd.)

Feeding Conditions: fasting for 20 hours from the previous day

Dose: 100 mg/body (in terms of the compound 1)

Administration method: administered with 50 mL water

Pretreatment: Pentagastrin was intramuscularly administered (10 μg/0.1mL/kg) 30 minutes before administering the formulation and thereafteradministered twice at an interval of 45 minutes. An atropine sulfateintravenous injection was intravenously administered (20 μg/0.04 mL/kg)30 minutes before administering the formulation.

The results are shown in Table 9.

TABLE 9 AUC ng · hr/mL Formulation Example 5 6842 Comparative Example 45789 Comparative Example 5 1666

As shown in Table 9, it was found that the absorption of the mesylatesalt of the o compound 1 is improved by the addition of HP-β-CD, and thephysically mixed product of the mesylate salt of the compound 1 andHP-β-CD shows absorbability comparable to the spray-dried product.

[Test Example 8] Absorbability Test 2 Formulation Example 6

Granulation was performed using a fluidized bed granulator (FL-LABO(special), manufactured by Freund Corporation) while spraying a 5%hydroxypropyl cellulose solution (1000 g) onto a mesylate salt of thecompound 1 (296.3 g), HP-β-CD (1350 g), and light anhydrous silicic acid(8.8 g), whereby a granulated material was obtained. Magnesium stearate(10 g) was added to the granulated material and mixed in a polyethylenebag, whereby granules were obtained.

The compositions of Formulation Example 5 and Formulation Example 6 areshown in Table 10.

TABLE 10 Formulation Formulation (unit: parts by mass) Example 5 Example6 Mesylate salt of Compound 1 1.0 1.0 HP-β-CD 4.6 4.6 Light anhydroussilicic acid — 0.03 Hydroxypropyl cellulose — 0.17 Magnesium stearate —0.03

With respect to Formulation Example 5 and Formulation Example 6, eachformulation was administered to animals under the following conditions,and the absorbability was evaluated.

Animals used: beagle dogs (3 male animals, Kitayama Labes Co., Ltd.)

Feeding Conditions: fasting for 20 hours from the previous day

Dose: 400 mg/body (in terms of the compound 1)

Administration method: administered with 50 mL water

Pretreatment: Pentagastrin was intramuscularly administered (10 μg/0.1mL/kg) 30 minutes before administering the formulation and thereafteradministered twice at an interval of 45 minutes. An atropine sulfateintravenous injection was intravenously administered (20 μg/0.04 mL/kg)30 minutes before administering the formulation.

The results are shown in Table 11.

TABLE 11 AUC ng · hr/mL Formulation Example 5 11258 Formulation Example6 12810

As shown in Table 11, it was found that the granules obtained bygranulating the mesylate salt of the compound 1 and HP-β-CD showabsorbability comparable to the physically mixed product thereof.

[Test Example 9] Absorbability Test 3 Formulation Example 7

Granulation was performed using a fluidized bed granulator (NFLO-5,manufactured by Freund Corporation) while spraying a 5% hydroxypropylcellulose solution (3000 g) onto a mesylate salt of the compound 1(888.8 g), HP-β-CD (4050 g), and light anhydrous silicic acid (26.3 g),whereby a granulated material was obtained. Two batches of thegranulated material were mixed using a mixer (CV-20, manufactured byTokuju Corporation) with magnesium stearate (60 g), whereby granuleswere obtained.

Formulation Example 8

Granulation was performed using a fluidized bed granulator (NFLO-5,manufactured by Freund Corporation) while spraying a 5% hydroxypropylcellulose solution (3000 g) onto a mesylate salt of the compound 1(888.8 g), HP-β-CD (4050 g), and light anhydrous silicic is acid (26.3g), whereby a granulated material was obtained. Magnesium stearate (2.16g) was added to a portion (396.4 g) of the granulated material and mixedin a polyethylene bag, whereby granules were obtained. The granules werecompressed into tablets with a diameter of 4 mm using a tabletingmachine (VELG 0512SW2MZ, manufactured by Kikusui Seisakusho Ltd.), andthereafter, a coating solution obtained by adding water (480.0 g),hypromellose (32.0 g), macrogol 6000 (4.0 g), titanium oxide (4.0 g),and yellow ferric oxide (0.2 g) was sprayed thereon using a coatingmachine (HC-FZ-LABO, manufactured by Freund Corporation), whereby coatedtablets of the tablets with a diameter of 4 mm were obtained.

Formulation Example 9

A portion (292.1 g) of the granules obtained in Formulation Example 7were compressed into tablets with a diameter of 3.5 mm using a tabletingmachine (VELG 0512SW2MZ, manufactured by Kikusui Seisakusho Ltd.), andthereafter, a coating solution obtained by adding water (540.0 g),hypromellose (48.0 g), macrogol 6000 (6.0 g), titanium oxide (6.0 g),and yellow ferric oxide (0.3 g) was sprayed thereon using a coatingmachine (HC-FZ-LABO, manufactured by Freund Corporation), whereby coatedtablets of the tablets with a diameter of 3.5 mm were obtained.

The compositions and dosage forms of Formulation Examples 7 to 9 areshown in Table 12.

TABLE 12 Formulation Formulation Formulation (unit: parts by mass)Example 7 Example 8 Example 9 Mesylate salt of Compound 1 1.0 1.0 1.0HP-β-CD 4.6 4.6 4.6 Light anhydrous silicic acid 0.030 0.030 0.030Hydroxypropyl cellulose 0.17 0.17 0.17 Magnesium stearate 0.034 0.0310.031 Hypromellose — 0.14 0.14 Macrogol 6000 — 0.017 0.017 Titaniumoxide — 0.017 0.017 Yellow ferric oxide — 0.00084 0.00084 Dosage formGranule Tablet with Tablet with diameter of diameter of 4 mm 3.5 mm

With respect to these, each formulation was administered to animalsunder the following conditions, and the absorbability was evaluated.

Animals used: beagle dogs (6 male animals, Kitayama Labes Co., Ltd.)

Feeding Conditions: fasting for 20 hours from the previous day

Dose: 200 mg/body (in terms of the compound 1)

Administration method: administered with 50 mL water

Pretreatment: An atropine sulfate intravenous injection wasintravenously administered (20 μg/0.04 mL/kg) 30 minutes beforeadministering the formulation. When the test was performed at a lowintragastric pH, pentagastrin was intramuscularly administered (10μg/0.1 mL/kg) 30 minutes before administering the formulation andthereafter administered twice at an interval of 45 minutes, and when thetest was performed at a high intragastric pH, omeprazole wasintravenously administered (1 mg/0.25 mL/kg) 30 minutes beforeadministering the formulation and 60 minutes thereafter once.

As a result, it was found that the tablets containing the mesylate saltof the compound 1 and HP-β-CD show absorbability comparable to thegranules thereof without being affected by the intragastric pH.

While the present invention has been described in detail with referenceto specific embodiments, it will be apparent to a person skilled in theart that various changes and modifications can be made without departingfrom the spirit and scope of the invention. This application is based onJapanese Patent Application filed on Feb. 15, 2017 (Patent ApplicationNo. 2017-026203), the entire contents of which are incorporated hereinby reference. Further, all references cited herein are incorporated byreference in their entirety.

1. A pharmaceutical composition, comprising:4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof; andhydroxypropyl-β-cyclodextrin.
 2. The pharmaceutical compositionaccording to claim 1, wherein the composition includes peaks at 5 ormore diffraction angles 2θ (±0.2°) selected from the group consisting of6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°) in powderX-ray structure diffraction.
 3. The pharmaceutical composition accordingto claim 1, wherein the composition includes peaks at diffraction angles2θ (±0.2°) of 6.5, 7.8, 9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°)in powder X-ray structure diffraction.
 4. The pharmaceutical compositionaccording to claim 1, wherein the composition includes peaks at chemicalshift values of 162.6, 130.4, 103.1, 82.7, 73.3, 41.9, and 19.9 in solid¹³C-NMR.
 5. The pharmaceutical composition according to claim 1, whereinthe composition includes peaks at 5 or more absorption bands selectedfrom the group consisting of 1663, 1352, 1225, 1156, 1032, 720, and 553(cm⁻¹) in an infrared absorption spectrum.
 6. The pharmaceuticalcomposition according to claim 1, wherein hydroxypropyl-β-cyclodextrinis contained at 0.1 to 5.5 parts by mass with respect to 1 part by massof4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof.
 7. The pharmaceuticalcomposition according to claim 1, further comprising: a silicic acidderivative.
 8. The pharmaceutical composition according to claim 1,further comprising: a cellulose derivative. 9-12. (canceled)
 13. Apharmaceutical composition, comprising:4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof; andhydroxypropyl-β-cyclodextrin, wherein the pharmaceutical composition isproduced by physical mixing.
 14. The pharmaceutical compositionaccording to claim 13, wherein the physical mixing is a productionmethod that does not include a step in which 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof is converted into asolution state when the pharmaceutical composition is produced.
 15. Thepharmaceutical composition according to claim 13, wherein the physicalmixing is mixing or granulation. 16-18. (canceled)
 19. Thepharmaceutical composition according to claim 13, wherein thecomposition includes peaks at 5 or more diffraction angles 2θ (±0.2°)selected from the group consisting of 6.5, 7.8, 9.6, 12.4, 18.8, 21.2,23.0, 24.5, and 26.0 (°) in powder X-ray structure diffraction.
 20. Thepharmaceutical composition according to claim 13, wherein thecomposition includes peaks at diffraction angles 2θ (±0.2°) of 6.5, 7.8,9.6, 12.4, 18.8, 21.2, 23.0, 24.5, and 26.0 (°) in powder X-raystructure diffraction.
 21. The pharmaceutical composition according toclaim 13, wherein the composition includes peaks at chemical shiftvalues of 162.6, 130.4, 103.1, 82.7, 73.3, 41.9, and 19.9 in solid¹³C-NMR.
 22. The pharmaceutical composition according to claim 13,wherein the composition includes peaks at 5 or more absorption bandsselected from the group consisting of 1663, 1352, 1225, 1156, 1032, 720,and 553 (cm⁻¹) in an infrared absorption spectrum.
 23. Thepharmaceutical composition according to claim 13, whereinhydroxypropyl-β-cyclodextrin is contained at 0.1 to 5.5 parts by masswith respect to 1 part by mass of a mesylate salt of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide.24. The pharmaceutical composition according to claim 13, furthercomprising: a silicic acid derivative.
 25. The pharmaceuticalcomposition according to claim 13, further comprising: a cellulosederivative. 26-29. (canceled)
 30. A method for producing apharmaceutical composition, comprising performing physical mixing of4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof andhydroxypropyl-β-cyclodextrin
 31. The production method according toclaim 30, wherein the physical mixing is a production method that doesnot include a step in which 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamideor a pharmaceutically acceptable salt thereof is converted into asolution state when the pharmaceutical composition is produced.
 32. Theproduction method according to claim 30, wherein the physical mixing ismixing or granulation. 33-35. (canceled)